Journal Article

A novel small-molecule PROTAC selectively promotes tau clearance to improve cognitive functions in Alzheimer-like models

Li, Shihong, Wang, Yipeng, Zheng, Jie, Wang, Weijin, Wang, Xin, Zhou, Qiuzhi, Ke, Dan, Wang, Jian-Zhi, Deng, Minmin, Wang, Qun, Ye, Jinwang, Jiang, Tao, Liu, Yanchao

2021

Overview

Intracellular accumulation of tau is a hallmark pathology in Alzheimer disease (AD) and the related tauopathies, thus targeting tau could be promising for drug development. Proteolysis Targeting Chimera (PROTAC) is a novel drug discovery strategy for selective protein degradation from within cells. A novel small-molecule PROTAC, named as C004019 with a molecular mass of 1,035.29 dalton, was designed to simultaneously recruite tau and E3-ligase (Vhl) and thus to selectively enhance ubiquitination and proteolysis of tau proteins. Western blotting, immunofluoresence and immunohistochemical staining were employed to verify the effects of C004019 in cell models (HEK293 and SH-SY5Y) and mouse models (hTau-transgenic and 3xTg-AD), respectively. The cognitive capacity of the mice was assessed by a suite of behavior experiments. Electrophysiology and Golgi staining were used to evaluate the synaptic plasticity. C004019 induced a robust tau clearance promoting its ubiquitination-proteasome-dependent proteolysis in HEK293 cells with stable or transient overexpression of human tau (hTau), and in SH-SY5Y that constitutively overexpress hTau. Furthermore, intracerebral ventricular infusion of C004019 induced a robust tau clearance . Most importantly, both single-dose and multiple-doses (once per 6 days for a total 5 times) subcutaneous administration of C004019 remarkably decreased tau levels in the brains of wild-type, hTau-transgenic and 3xTg-AD mice with improvement of synaptic and cognitive functions. The PROTAC (C004019) created in the current study can selectively and efficiently promote tau clearance both and , which provides a promising drug candidate for AD and the related tauopathies.

• Publisher: Ivyspring International Publisher Pty Ltd,Ivyspring International Publisher
• Subject: Alzheimer Disease - drug therapy / Alzheimer Disease - metabolism / Animals / Brain / Brain - drug effects / Brain - metabolism / Cell Line / Cognition - drug effects / Disease Models, Animal / Drug development / Drug dosages / HEK293 Cells / Humans / Kinases / Male / Mice / Mice, Inbred C57BL / Mice, Transgenic / Neuronal Plasticity - drug effects / Neurons - drug effects / Neurons - metabolism / Proteasome Endopeptidase Complex - drug effects / Proteasome Endopeptidase Complex - metabolism / Proteins / Proteolysis - drug effects / Research Paper / Small Molecule Libraries - pharmacology / tau Proteins - metabolism / Tauopathies - drug therapy / Tauopathies - metabolism / Ubiquitination - drug effects